The present invention relates to a novel use of benzazepine-N-acetic acid derivatives which contain an oxo-group in the α-position to the nitrogen atom and are substituted in position 3 by a 1-(carboxyalkyl)cyclopentylcarbonylamino radical, and/or of their salts and biolabile esters, and/or of physiologically acceptable solvates thereof in larger mammals and particularly in humans, especially human patients having diabetes, and to the production of pharmaceutical compositions and products suitable for the novel treatment.
Benzazepine-N-acetic acid derivatives which contain an oxo group in α-position to the nitrogen atom and are substituted in position 3 by a 1-(carboxyalkyl)cyclopentyl-carbonylamino radical, and their salts and biolabile esters fall within the scope of the benzazepine, benzoxazepine and benzothiazepine-N-acetic acid derivatives which contain an oxo group in the α-position to the nitrogen atom and are substituted in position 3 by a 1-(carboxyalkyl)cyclopentylcarbonylamino radical and have NEP-inhibitory effects on the heart, as described in U.S. Pat. No. 5,677,297 (=DE 195 10 566 and EP 733,642). The benzazepine-N-acetic acid compounds used in the context of the present invention can be produced by the methods described in U.S. Pat. No. 5,677,297, which is incorporated herein by reference. Furthermore, the cause of the hypertension to be treated can have a wide variety of origins. Besides essential hypertension (primary hypertension), there are also forms of secondary hypertension which may occur as a result of various non-cardiac diseases, which may be also treated with the afore-mentioned benzazepine-N-acetic acid derivatives as described e.g. in U.S. Pat. No. 6,482,820 (=WO 00/48601 or EP 1154777).
The disclosure of U.S. Pat. No. 5,783,573 also embraces benzazepine-N-acetic acid derivatives, which contain an oxo-group in the α-position to the nitrogen atom and are substituted in position 3 by a 1-(carboxyalkyl)cyclopentylcarbonylamino radical, e.g. a reference is made to the use of such compounds in the improvement of gastrointenstinal blood circulation (mesenteric blood flow). Reduced gastrointestinal blood flow can be caused by many different reasons, e.g. an increased vascular resistance of blood vessels which supply the gastrointestinal region or pathological changes in vascular function which can be connected to diabetes and/or cardiac diseases such as hypertensive cardiomyopathy.
Furthermore, in the state of the art the combined inhibition of neutral endopeptidase with angiotensin converting enzyme or endothelin converting enzyme in experimental diabetes is described by Tikkanen I. et al. (Journal of Hypertension 2002, 20: 707–714), however the described effects in relation to diabetes in the used streptozotocin-induced diabetic Sprague-Dawley rat model seem to be secondary to the blood pressure reduction by the compounds administered by Tikkanen I. et al.